DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for peroxisome biogenesis disorder — screening already-approved drugs against its 16-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease modulePeroxisome biogenesis disorder maps to a 16-gene Open Targets module — the target space DeCure's AI scientist screens approved drugs against.
DeCure.ai methodSignature reversal (LINCS) plus network proximity (STRING) rank already-approved drugs likely to perturb this module — the same engine that produces DeCure.ai's repurposing hypotheses.
Repurposing thesisScreening approved medicines against this disease module, then publishing the evidence for the strongest candidate. Known pharmacology and human exposure data make the first question sharper — they do not establish safety or efficacy in a new indication.
Research record
01
ResearchComing soon
Candidate research + dossier — target rationale, drug-repurposing thesis and evidence pack.proof: Published dossier + on-chain hash
02
ValidationComing soon
In-vitro biological validation at a contract research org (CRO).proof: CRO contract + in-vitro report
03
Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash
Current lead
approvedL-CarnitineUnknown
Structures already discussed alongside peroxisome biogenesis disorder in the retrieved literature, rendered from public PubChem SMILES. Which drugs appear here reflects the evidence found, not a ranked prediction.
Molecular view
betaine--homocysteine S-methyltransferase (BHMT) — BHMT is one of the genes in this disease's Open Targets module — part of the target space DeCure's repurposing candidates point at. The protein backbone is drawn as a cartoon. The structure has 2-amino-4-mercapto-butyric acid bound in it, shown as sticks.
Loading structure…
helix sheet hcsdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 4M3P · 1.895 Å · ligand 2-AMINO-4-MERCAPTO-BUTYRIC ACID (HCS). Experimental structure, not a prediction.
What the evidence adds up to
Peroxisome biogenesis disorders are caused by defects in PEX genes, which encode peroxins required for peroxisome assembly. No curative therapy or long-term effective treatment currently exists. A 2008 study of 11 fibroblast cell lines from patients with PEX5 mutations identified 11 different mutations, eight novel, and correlated mutation location with the specific protein import defect observed. Six cell lines had defects in both PTS1 and PTS2 protein import, while four had defects only in PTS1 import.
High-content screening of chemical libraries identified small molecules active at micromolar concentrations that rescued peroxisome functions in patient cells, based on cell imaging, biochemical, and protein processing assays. However, these findings are from cell models only. Patient-derived fibroblasts and Pex gene knockout mice do not represent exact human mutations or most clinical aspects of the disease.
Induced pluripotent stem cells have been generated from patient fibroblasts and differentiated into central nervous system cell lineages and hepatocyte lineages, showing peroxisomal protein defects in the derived cells. A Pex1-p.G844D mouse was characterised as the first mouse model with hypomorphic PEX alleles, and gene expression profiling of the murine retina suggested the mice could serve as a model for investigating retinal gene therapy. CRISPR-Cas9 base editing was used to introduce and correct the common PEX1-p.G843D mutation in HepG2 cells, with preliminary evidence suggesting both introduction and correction are possible and efficient.
What is still missing is a therapy that has been tested in humans and shown to alter disease course. The available models — fibroblasts, iPSC-derived cells, HepG2 lines, and the hypomorphic mouse — have not yet yielded a compound that has moved into clinical trials. Funding for rare disease drug development, trial design for ultra-rare populations, and patient stratification by specific PEX mutation and residual function remain unresolved.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
European Journal of Biochemistry · 1992 · 35 citations · open access
Carnitine biosynthesis in hepatic peroxisomes
AbstractWe have investigated whether hepatic peroxisomes are capable of synthesizing carnitine. When purified peroxisomes were incubated with gamma-butyrobetaine, a precursor of carnitine, formation of carnitine was observed. These results indicate that peroxisomes contain gamma-butyrobetaine hydroxylase, the enzyme which catalyzes the final step in the biosynthesis of carnitine. This enzyme was previously believed to be present only in the cytosol. gamma-Butyrobetaine hydroxylase activity in peroxisomes was not due to cytosolic contamination as evaluated by marker enzyme analysis. When proliferation of peroxisomes was induced by clofibrate treatment, gamma-butyrobetaine hydroxylase/mass liver increased by 7.6-fold and the specific activity by 2.5-fold. We conclude that hepatic peroxisomes synthesize carnitine and this synthesis becomes substantial under conditions of peroxisomal proliferation.
Genotype-phenotype correlation in PEX5-deficient peroxisome biogenesis defective cell lines
AbstractProteins destined for the peroxisomal matrix are targeted by virtue of a peroxisomal targeting sequence type 1 (PTS1) or type 2 (PTS2). In humans, targeting of either class of proteins relies on a cytosolic receptor protein encoded by the PEX5 gene. Alternative splicing of PEX5 results in two protein variants, PEX5S and PEX5L. PEX5S is exclusively involved in PTS1 protein import, whereas PEX5L mediates the import of both PTS1 and PTS2 proteins. Genetic complementation testing with over 500 different fibroblast cell lines from patients diagnosed with a peroxisome biogenesis disorder (PBD) identified 11 cell lines with a defect in PEX5. The aim of this study was to characterize these cell lines at a biochemical and genetic level. To this end, the cultured fibroblasts were analyzed for very long chain fatty acid (VLCFA) concentrations, peroxisomal beta-and alpha-oxidation, dihydroxyacetone-phosphate acyltransferase (DHAPAT) activity, peroxisomal thiolase, and catalase immunofluorescence. Mutation analysis of the PEX5 gene revealed 11 different mutations, eight of which are novel. PTS1- and PTS2-protein import capacity was assessed by transfection of the cells with green fluorescent protein (GFP) tagged with either PTS1 or PTS2. Six cell lines showed a defect in both PTS1 and PTS2 protein import, whereas four cell lines only showed a defect in PTS1 protein import. The location of the different mutations within the PEX5 amino acid sequence correlates rather well with the peroxisomal protein import defect observed in the cell lines.
Cell Biochemistry and Function · 2004 · 6 citations
Carnitine prevents cyclic GMP‐induced inhibition of peroxisomal enzyme activities
AbstractPeroxisomes, also termed as microbodies, are now known to carry out several specialized metabolic activities that are vital to cellular function. A defect in peroxisomal function leads to development of a fatal human disease, and a number of peroxisomal disorders are now linked to inherited peroxisomal enzyme abnormalities. Peroxisomal enzyme activities are also altered during pathophysiological conditions through various endogenously produced bio-molecules such as nitric oxide (NO). NO produced by cytokines or NO-donors is known to modulate peroxisomal functions, and these effects of NO are mediated through cGMP. We are reporting for the first time that L-carnitine (1-5 mm) prevents cGMP-mediated impairment of peroxisomal enzyme activities. Cyclic GMP (250-1000 muM) significantly inhibited (p < 0.01) the specific activities of catalase, acyl CoA oxidase and dihydroxyacetone-phosphate acyltransferase (DHAPATase) in human dermal fibroblasts, and treatment of cells with 1-5 mM of carnitine significantly (p < 0.001) reduced the inhibitory effects of cGMP on peroxisomal enzyme activities. These findings suggest that carnitine, previously thought to participate only in fatty acid oxidation, may in fact be regulating other cellular events including oxidative stress, and could possibly be used to correct cytokine-impaired peroxisomal functions.
University of Southern California Digital Library · 2012 · 0 citations · open access
IPS and CNS cell models of peroxisomal disorders
AbstractPeroxisomal disorders are a group of genetically heterogeneous metabolic diseases caused by defects in peroxins, proteins encoded by PEX genes that function in peroxisome biogenesis, or in a single peroxisomal protein that has a more targeted effect on specific peroxisome functions. In general, peroxisome disorders can affect almost every organ system, with especially devastating effects on the nervous, hepatic, and adrenocortical systems. ? Currently, there is no curative therapy or long-term effective treatment available for peroxisomal disorders. Ongoing pathomechanism studies, diagnostics, and drug testing are mainly established on patient-derived primary fibroblasts and Pex gene knockout mouse models, which do not represent the exact human mutations and most clinical aspects of the human disease. ? In this thesis, I describe a new model system which we established for studying the pathology of peroxisomal disorders and testing new therapeutic agents. We generated induced pluripotent stem cells (iPSCs) from primary skin fibroblasts of multiple healthy controls and patients with peroxisomal biogenesis disorders (PBD), caused by genetic defects in PEX genes, or the childhood cerebral form of X-linked adrenoleukodystrophy (CCALD), caused by genetic defects in the ABCD1 gene that encodes a peroxisome membrane protein involved in very long chain fatty acid (VLCFA) metabolism. Candidate iPSCs were subject to global expression, DNA methylation, and genotyping analysis and tested for pluripotency through in vitro embryoid body differentiation and in vivo teratoma formation. We characterized the gene expression and biochemical profiles of these patient-specific iPSCs and further differentiated these iPSCs into pathologically related central nervous system cell (CNSC) lineages, including neural progenitors, motor neurons, and oligodendrocytes. ? Our molecular characterization of iPSCs and CNSCs provided a novel perspective into disease mechanisms that supports leading hypotheses regarding disease pathogenesis including the pivotal roles of neuroinflammation, lipid metabolism, and aberrant mitochondrial function. Our novel resources also provide a first step required for the development and interpretation of patient-specific model systems that investigate non-cell autonomous processes relevant to the etiology of peroxisomal disorders. These iPSC and CNS cell resources could also have applications for high content screening (HCS) of chemical libraries for candidate drugs that directly address the cell type specificity of disease and the nature of the mutations found in the patient population.
AbstractABSTRACT First Person is a series of interviews with the first authors of a selection of papers published in Disease Models & Mechanisms, helping researchers promote themselves alongside their papers. Vanessa Gomez is first author on ‘ Distinguishing PEX gene variant severity for mild, severe, and atypical peroxisome biogenesis disorders’, published in DMM. Vanessa is a Research Assistant in the lab of Michael F. Wangler at Baylor College of Medicine, Houston, TX, investigating rare human disease phenotypes to advance our understanding of biological principles that govern health and disease.
University of Southern California Digital Library · 2016 · 0 citations · open access
Development of targeted therapies for peroxisome biogenesis disorders
AbstractPeroxisome biogenesis disorders (PBDs) are a group of genetically heterogeneous rare metabolic diseases caused by defects in peroxins, proteins encoded by PEX genes that function in peroxisome biogenesis. PBDs display an autosomal recessive mode of transmission with an estimated incidence of 1 in 50,000 births in America. Although the genetic basis of PBDs is well understood, there is currently no curative therapy or long-term effective treatment available. ? In this dissertation, I described the identification and characterization of small molecules that enhance peroxisome assembly and function in PBD patient cells through high-content screening (HCS) of chemical libraries. Our therapeutic hypothesis is that the rescue of peroxisome assembly and functions will be of therapeutic benefit to individuals with peroxisome biogenesis disorders. We uncovered a novel group of compounds active at the micromolar range that rescued peroxisome functions in patient cells based on cell imaging, biochemical, and protein processing assays. Overall, the novel bioactive small molecules we identified could provide tools for investigating peroxisome biogenesis and novel leads for the development of targeted small molecule therapies, and the new cellular and animal models can be the next generation screening tools to discover and characterize more active compounds. ? In addition, I describe the development of new model systems of PBDs, including induced pluripotent stem cells (iPSCs), HepG2 cells and mice. We generated iPSCs from primary skin fibroblasts of PBD patients and differentiated them into central nervous system (CNS) and hepatocyte cell lineages and showed peroxisomal protein defects of the derived cells. We also generated and characterized HepG2 PEX1 mutant cell lines with peroxisome assembly defects. Finally, I also participated in the characterization of the Pex1-p.G844D mouse which is the first mouse model with hypomorphic PEX alleles and thus better disease model for PBD patients with milder clinical features. Gene expression profiling of the murine retina and the recovery of peroxisomal protein import by adeno-associated virus (AAV)-mediated gene expression suggested that the mice can serve as a powerful model system for investigating retinal gene therapy. Overall, These iPSC, iPSC-derived cells, murine model skin fibroblast and HepG2 cells carrying common PEX1 mutations can have future applications for chemical library screening for candidate drugs that directly address the cell type specificity of disease and the nature of the mutations found in the patient population.
University of Southern California Digital Library · 2019 · 0 citations · open access
Developing novel in vitro model systems to investigate therapeutic hypotheses for peroxisome biogenesis disorders
AbstractPeroxisomes are microbody organelles present in virtually all cells of eukaryotic organisms. They play vital roles in numerous metabolic pathways including the catabolism of very long chain fatty acids (VLCFAs) as well as the biogenesis of docosahexaenoic acid (DHA) and plasmalogens. Proper assembly and function of peroxisomes is essential to human health and development. The importance of proper peroxisome function is highlighted by a number of multi-systemic disorders in humans that result from inherited mutations in peroxisome-related genes, collectively referred to as peroxisome biogenesis disorders (PBDs). Peroxisome biogenesis disorders affect the body globally, although certain organ systems that rely more heavily on peroxisome-mediated metabolism are more seriously affected, including the nervous and hepatic systems. ? Currently, because primary cell models are inaccessible due to ethical dilemmas, it is difficult to study the mechanics of PBDs in the context of specific organ systems. The most common cell-based models for PBDs are derived from patient and genetically engineered mouse fibroblasts. Although these cells have proven invaluable for screening small molecule libraries, our goal is to establish and test cell models that more closely represent affected cell-types. We hypothesized that the widely utilized HepG2 liver-cancer immortalized cell-line carrying common PBD mutations may serve as a better model for testing the effects that drugs identified as possibly therapeutic in immortalized fibroblast models may have on liver function and health and better elucidate the mechanisms by which the rescue is occurring. We used CRISPR/Cas9 gene editing to introduce PEX1 null mutations in HepG2 cells via the introduction of double-strand breaks in PEX1. We were able to successfully generate two separate HepG2 cell lines, each homozygous for null PEX1, differing slightly in their specific mutations. ? We also explored the use of a new CRISPR-Cas9 base editing system, developed in David Liu?s laboratory at Harvard University, for its ability to both introduce and correct the most common PEX1 mutation, the PEX1-p.G843D mutation. This single-base pair mutation results in a hypomorph allele with limited gene function. Using the CRISPR-Cas9 base-editing system, we have preliminary evidence that suggests both introduction and correction of PEX1-p.G843D are possible and efficient. Further research is required to investigate the potential benefits to PBD research and therapeutic endeavors that this technology may make possible.
The Metabolic Role of Peroxisome in Health and Disease
AbstractPeroxisomes are cell organelles that have functions for the provision of homeostasis and sustainable cellular health. They are indispensable for lipid metabolism and free radical detoxification. A disruption in the peroxisomal pathway can cause irreparable problems or death for the organism. This book provides a comprehensive overview of peroxisomes, including their role in cell health and diseases such as cancer.
Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
DeCure is a research and publication project, not medical advice and not a treatment. "DeCure for X" describes a research goal, not a claim that a cure exists. Backing a cure is a contribution to fund the research — it is not an investment, and confers no yield, royalty, equity or IP ownership. Papers are published open-access by the DeCure.ai DAO.
